1, 3-bisaminoalkyl-3-phenyl-2, 5-dioxopyrrolidines



Patented Jan. 12 1954 1,3-BISAMINOALKYL-3-PHENYL-2,5-IlIOXO- PYRROLIDINES I Ernst Sury, Basel, and Karl Hoffmann, Binningen, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application September 8, 1952,

Serial No. 308,521

Claims priority, application Switzerland September 11, 195i 13 Claims. (01; 266-294.?)

The present invention relates to 1,3-bis-(tertiary amino-lower alkyl) 3 phenyl-2,5-dioxopyrrolidines and salts thereof. More particularly, the invention has especial relation to the quaternary ammonium salts of the aforesaid amines, since such salts exhibit curarizing properties and are accordingly useful as curariform agents.

The new compounds, in the base form, can be represented by the following general formula lkylenex "(v-piperidinopropyl) 2,5 dioxo pyrrolidine, which can be represented by the following formula:

con

Hal 0 N CH:

Hal

The aforementioned 1,3-bis-(tertiary aminolower alkyl)-3-phenyl-2,5-dioxo-pyrrolidines are made by converting a 2 phenyl 2 (tertiary aminoalkyl) -butane-1,4 -diacid mononitrile ester into its cyclic secondary imide and introducing into the 1-position of the resulting 3-phenyl-3- (secondary aminoalkyl) -2,5-dioxo-pyrrolidine a tertiary aminoalkyl radical.

The tertiary amines that is, the 1,3-bis-(tertiary amino-lower alkyD-S-phenyl 2,5 dioxopyrrolidines thus formed, are quaternized, for example, by reaction with reactive esters of alcohols, especially esters with hydrohalic acids, sulfuric acid or organic sulfonic acids, such as alkyl halides, dialkyl sulfates, and aliphatic or aromatic sulfonic acid esters.

In general, in practicing the process an appropriately substituted butane 1,4 diacid-mononitrile ester is used as starting material, and treated in the presence or absence of a solvent, such as glacial acetic acid or acetic anhydride, with a condensing agent such as concentrated sulfuric acid. Into the pyrrolidine unsubstituted at the ring nitrogen atom thus obtained, there is then introduced in the 1-position the tertiary amino alkyl radical, for example, by reaction with a tertiary aminoalkyl halide. This subsequent substitution is advantageously carried out in the presence of a condensing agent which is capable of forming metal compounds with the dioxo-pyrrolidines, such as an alkali metal amide, for example, sodamide.

The 1,3-bis-(tertiary aminoalkyl)-3-phenyl- 2,5-dioxo-pyrrolidines are readily quaternized by heating together with reactive esters of alcohols, .e. g. those hereinbefore mentioned.

The 2-phenyl-2-tertiary aminoalkyl-butane- -1,4-diacid mononitrile ester employed as a starting material can, for example, be prepared by condensing a phenyl-(tertiary aminoalkyD- acetic acid-nitrile with a bromo-acetic acid alkyl ester in theusual manner.

The following examples illustrate the invention, the parts being by weight unless otherwise stated and the relationship of parts by Weight to parts by volume being the same as that of the gram to the cubiccentimeter. Temperatures are in degrees centigrade.

' Example 1 45 parts of 2 phenyl 2 (p-diethylaminoethyl) butane-1A-diacid-mononitrile-(1)-ethyl ester are dissolved in 50 parts by volume of glacial acetic acid, then admixed with parts by volume of concentrated sulfuric acid, and the whole is heated for 15 minutes at -140 C. The dark colored reaction mixture is stirred into ice, adjusted to a pH value of 8-9 with aqueous ammonia, extracted with chloroform, and the chloroform solution is washed with Water, dried over calcium chloride and the solvent is evaporated. The viscous residue is distilled in a high 7 3 vacuum. The resulting 3-phenyl-3-(fi-diethylamino ethyl) 2,5 dioxo pyrrolidine of the formula boils at 215-221 C. under 0.3 mm. pressure, crystallizes upon standing, melts at 89-90 C. and forms an easily water-soluble hydrochloride.

20 parts of 3-phenyl --3 -(B diethylaminoethyl) -2,5-dioxo-pyrrolidine are caused to react in the presence of 4 parts of sodamide as condensing agent with 12 parts of fi-chlorethyldiethylamine in 300 parts by volume-oftoluene as solvent at 8090 while stirring well. The reaction mixture is further stirredat room temperature overnight, then the solvent is distilled off under reduced pressure, the residue is taken up in ether, and the ethereal solution is washed with water and dried over calcium chloride. The solvent is distilled oif and the oily residue is taken up in petroleum ether. Undissolved matter is removed by filtration, the solvent is evaporated and the residue is distilled in a high vacuum.

-3-ph,enyl 1,3 bis -(B-diethylamino-ethyl) 2,5-

dioxo--pyrrolidine of the formula vv2,5-dioxo pyrrolidine-bis-iodomethylate :of the formula I I I CHzClHzlTN C2115):

CHa

The 2-phenyl-2- (B-diethylamino-ethyl) -butane- 1,4-diacid-mononitrile-(1) -ethyl ester used as starting material in this example can be made, for example, by condensing 216 parts of phenyl- (B-diethylamino-ethyl)--acetic acid nitrile with 177 parts of :bromacetic acid ethyl ester in the presence of 45 parts of sodamide in 700 parts by volume of toluene. It boils at 155-l6l under 0.08 mm. pressure.

Example 2 parts of 2-phenyl-2-('y-diethylamino-propyl) -butane 1,4 diacid mononitrile-(1)-ethyl ester are dissolved in 150 parts by volume of glacial acetic acid, :then admixed with 150 parts by volume of concentrated sulfuric acid, the whole then heated for 15 minutes at 100-120. The dark colored reaction mixture is stirred into ice, ad-

justed to a pH of 8-9 with aqueous ammonia,

boils at -213-218;(0.05 mm.) It is a yellow viscous oil and forms a hydrochloride readily soluble in water.

20.0 parts of B-phenyl 3 -(ydiethylaminopropyl) -2,5-dioxo-pyrr01idine are dissolved in 250 parts by volume of absolute toluene, and 3.2 parts of powdered sodamide introduced while stirring in an atmosphere of nitrogen at a temperature of 90-110. With continued stirring, the reaction mixture is maintained at this temperature, and 12 parts of -chloropropyl-diethylamine, dissolved in 50 parts of toluene, are then added portionwise at 90, and the reaction mixture is finally maintained at 90-110 for 3 hours longer. After cooling, there is obtained by work- --ing up as prescribed in Example 1, the 'S-phenyl- 1,3-bis- -diethylamino-propyl) -2,5-dioxo pyrrolidine as ayellow, highly viscous oil boiling at 192-198 under 0.06 mm. pressure,

5 parts of '3-phenyl-1 ,3-bis-( -diethylamino- .propyl) -2,5-dioxopyrrolidine are dissolved in 25 .parts by volume of absolute ethyl acetate, methyl bromide is introduced until saturation is achieved,

the reaction m-ixture'is heated for a short time in a closed vessel on the water bath, then cooled,and

the 3-pheny1-l,3-bis (ydiethylamino-propyll- 2,5-dioxo-pyrrolidinebis-bromomethylate of the formula lZIi Example 3 140 parts of 2-phenyl-2-('y-piperidlno-propyl) butane- 1,4-diacid-mononitrile- 1) -ethylester are dissolved in 150 parts by volume of acetic acid, then admixed with 150 parts by volume of concentrated sulfuric acid, and the whole then heated for minutes at 100-120. The dark colored reaction mixture is stirred into ice, adjusted to a pH of 8-9 with aqueous ammonia, extracted with chloroform, and the chloroform solution is washed with water, dried over calcium chloride, and the solvent evaporated. The viscous residue is distilled under high vacuum. The resulting 3- phenyl 3 ('y piperidino-propyl) 2,5 dioxopyrrolidine of the formula CHzCHzCHzN boils at 233-237 (0.07 mm.). After recrystallization from methanol the compound melts at 131-132". It forms a water soluble hydrochloride.

30 parts of 3-phenyl-3-(- -piperidino-propyl)- 2,5-dioxo-pyrrolidine are dissolved in 300 parts by volume of absolute toluene, and 4.6 parts of powdered sodamide introduced in portions while stirring in an atmosphere of nitrogen at a reaction temperature of 100-ll0. The reaction mixture is maintained at this temperature for six hours while stirring, then parts of 'ychloropropyl-piperidine, dissolved in 50 parts by volume of toluene, are added in portionwise and the reaction mixture is finally maintained at a temperature of IOU-110 for another 6 hours. By working up as in Example 1, there is obtained the 3-phenyl-l,3bis('y-piperidino-propyl)-2,5- dioxo-pyrrolidine in the form of a yellowish oil which boils at 246-250 under 0.03 mm. pressure. The base can be characterized as a dihydrochloride which, when recrystallized from a mixture of methanol and ethyl acetate, melts at 236-237".

6. parts of 3-phenyl-1,3-bis-(' -piperidinopropyl) -2,5-dioxo-pyrrolidine are dissolved in 50 parts by volume of absolute ethyl acetate, 6 parts by volume of methyl iodide are added and the reaction mixture heated at 90 on the water bath for 15 minutes. The 3-phenyl-1,3-bis-(' -piperidino propyl) 2,5 dioxo pyrrolidine bis iodomethylate of the formula CHa which precipitates in the form of white needles is separated by filtration and recrystallized from a mixture of methanol and ethyl acetate. Its melting point is at 185-186.

The 2-phenyl-2-('y-piperidino-pr0py1) -butane- 1,4-diacid-mononitrile-(1)-ethyl ester used as a starting material in this example can be made,

for example, by condensing 121 parts of phenyl- -piperidino-propyl)-acetic acid-nitrile with 92 parts of bromoacetic acid ethyl ester in the presence of 23 parts of sodamide in 500 parts by volume of absolute ether. It boils at -190 (0.07 mm.).

Example 4 In the same manner as described in Example 3 8.4 parts of 3-phenyl-1,3-bis-(y-piperidinopropyl)-2,5-dioxo-pyrrolidine, dissolved in 50 parts by volume of ethyl acetate, are reacted with 10 parts of methylbromide in a sealed tube for hour at 45-50% B-phenyl-lB-bis-(ypiperidino propyl) 2,5 dioxo pyrrolidinebis-bromomethylate is formed. It has the formula HzCHzCHzN After recrystallization from isopropanol-ethyl acetate the colorless needles melt at 171-176".

Example 5 CH2CH2CH2N I CHaCHaCHaN It melts after recrystallization from isopropanolethylacetate at 225-229".

What is claimed is:

1. A compound selected from the group consisting of 3-phenyl-1,3-bis- [di- (lower-alkyl) -aminolower alkyl] 2,5 dioxo-pyrrolidines, 3-phenyl- 1,3 bis (piperidino lower alkyl) 2,5- dioxo-pyrrolidines, the bis-acid-addition-salts and therapeutically applicable bis-lower-alkyl quaternary ammonium salts thereof.

2. 1,3 bis [di (lower alkyl) aminolower alkyl]-3-phenyl-2,5-dioxo-pyrrolidines.

3. The therapeutically applicable bis-lower alkyl-quaternary ammonium salts of the compounds of claim 2.

4. The bis-loWer-halogenalkylates of the compounds of claim 2.

5. The bis-halogenomethylates of the compounds of claim 2.

6. 3 phenyl 1,3-bis di-lower alkylamino lower-alkyl)-2,5-dioxo-pyrrolidines.

L alkyl) -2,5-di0Xo-pyrro1idines. 9. The bis-lower-halogenalkylates of the compounds of claim 8.

10. 3 phenyl 1,3 bis (fi diethylaminoethyl) 2,5 dioxo pyrrolidins bis halogenomethylate.

'11. 3 phenyl 1,3 bis (v diethylaminopropyD 2,5 dioxo pyrrolidinv bis halogenomethylate.

12. 3 phenyl 1,3 bis ('y piperidinopropyl) 12,5 dioxo pyrrolidine his halogenamethylate,

13. 3 phenyl 1,3 bis ('y piperidinopropyl) 2,5 dioxo pyrrolidine bis iodomethylate.

T V ERNST SURY.

KARL HOFFMANN.

References Cited in the file of this patent V UNITED STATES PATENTS Number Name 'Date 2,555,353 Lucas etal. June 5, 1951 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-PHENYL-1,3-BIS-(DI-(LOWER-ALKYL) -AMINOLOWER ALKYL) - 2,5 - DIOXO-PYRROLIDINES, 3-PHENYL1,3 - BIS - (PIPERIDINO - LOWER - ALKYL) - 2,5DIOXO-PYRROLIDINES, THE BIS-ACID-ADDITION-SALTS AND THERAPEUTICALLY APPLICABLE BIS-LOWER-ALKYL QUATERNARY AMMONIUM SALTS THEREOF. 